June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Efficacy of Complement C3 Inhibition in Preclinical Models of Wet Age-related Macular Degeneration (AMD)
Author Affiliations & Notes
  • Wei-Sheng Chen
    Ophthalmology, NGM Biopharmaceuticals, Inc., South San Francisco, California, United States
  • Benbo Song
    NGM Biopharmaceuticals, California, United States
  • Mary-Kamala Isoka
    Ophthalmology, NGM Biopharmaceuticals, Inc., South San Francisco, California, United States
  • Maria Bogachek
    Ophthalmology, NGM Biopharmaceuticals, Inc., South San Francisco, California, United States
  • Betty Li
    NGM Biopharmaceuticals, California, United States
  • Kalyani Mondal
    NGM Biopharmaceuticals, California, United States
  • Yan Wang
    NGM Biopharmaceuticals, California, United States
  • Serena Leong
    NGM Biopharmaceuticals, California, United States
  • Darrin Lindhout
    NGM Biopharmaceuticals, California, United States
  • Bin Fan
    NGM Biopharmaceuticals, California, United States
  • Raj Haldankar
    NGM Biopharmaceuticals, California, United States
  • Jie Tang
    NGM Biopharmaceuticals, California, United States
  • David Shen
    NGM Biopharmaceuticals, California, United States
  • Hui Tian
    NGM Biopharmaceuticals, California, United States
  • Zhonghao Liu
    NGM Biopharmaceuticals, California, United States
  • Alexander Loktev
    Ophthalmology, NGM Biopharmaceuticals, Inc., South San Francisco, California, United States
  • Footnotes
    Commercial Relationships   Wei-Sheng Chen, NGM Biopharmaceuticals (E); Benbo Song, NGM Biopharmaceuticals (E); Mary-Kamala Isoka, NGM Biopharmaceuticals (E); Maria Bogachek, NGM Biopharmaceuticals (E); Betty Li, NGM Biopharmaceuticals (E); Kalyani Mondal, NGM Biopharmaceuticals (E); Yan Wang, NGM Biopharmaceuticals (E); Serena Leong, NGM Biopharmaceuticals (E); Darrin Lindhout, NGM Biopharmaceuticals (E); Bin Fan, NGM Biopharmaceuticals (E); Raj Haldankar, NGM Biopharmaceuticals (E); Jie Tang, NGM Biopharmaceuticals (E); David Shen, NGM Biopharmaceuticals (E); Hui Tian, NGM Biopharmaceuticals (E); Zhonghao Liu, NGM Biopharmaceuticals (E); Alexander Loktev, NGM Biopharmaceuticals (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1799. doi:
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      Wei-Sheng Chen, Benbo Song, Mary-Kamala Isoka, Maria Bogachek, Betty Li, Kalyani Mondal, Yan Wang, Serena Leong, Darrin Lindhout, Bin Fan, Raj Haldankar, Jie Tang, David Shen, Hui Tian, Zhonghao Liu, Alexander Loktev; Efficacy of Complement C3 Inhibition in Preclinical Models of Wet Age-related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2020;61(7):1799.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Several lines of evidence, including human genetics, animal models, and recent clinical trial results, implicate complement system dysregulation in the pathogenesis of AMD. Published preclinical studies demonstrated the potential benefit of complement inhibition, at various points in the pathway, in rodent models of neovascular AMD. However, despite the central role of complement factor C3 (C3) in the activation of complement cascade, pharmacological intervention to inhibit C3 in these models remains largely unexplored. The goal of this study was to examine the effects of pharmacological and genetic inhibition of C3 in a rodent choroidal neovascularization (CNV) model.

Methods : We used an image-guided laser-induced CNV model in C57BL/6 wild type and C3-/- mice (JAX Stock #32042, backcrossed to C57BL/6 mice). Pharmacological inhibition of C3 was achieved by intravitreal (IVT) administration of an inhibitory anti-mouse C3 antibody one day prior to laser treatment. Seven days after laser was used to rupture Bruch’s membrane and induce CNV, vascular leakage was quantified by fluorescein angiography (FA) and CNV lesion size measured in eyecup flat-mounts stained with isolectin B4.

Results : Genetic ablation and pharmacological inhibition of C3 resulted in improved phenotypes in laser-induced CNV models. Specifically, CNV leakage was reduced by 52% in C3-/- mice compared to wild-type control mice. Comparable results (38% reduction) were achieved with a single IVT injection of an anti-C3 inhibitory antibody. Reduction in CNV lesion size failed to reach statistical significance in these studies.

Conclusions : We demonstrate that C3 deficiency/inhibition reduces vascular leakage in the rodent laser-induced CNV model, suggesting the therapeutic potential for C3 inhibition for neovascular AMD. We continue to investigate the mechanism through which complement inhibition affects the progression of angiogenesis in response to acute injury.

This is a 2020 ARVO Annual Meeting abstract.

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